The present invention relates generally to apparatus for synthesizing and processing chemical and biological compounds, and to multi-well apparatus used in performing multiwell simultaneous synthesis.
The testing and analysis of chemical compounds on a micro scale has many advantages. Among these are the reduced costs of reagents, solvents and materials due to the reduced amounts needed, and the generation of less waste materials, which may be environmentally damaging and costly to dispose of. The reduction in volume of material necessary also allows for easier use of multiple reaction vessels within a single apparatus, so that devices having arrays of multiple wells are being used more and more. Standardization has begun in this field, so that a format of 96 wells in an 8xc3x9712 rectangular array is used in a large variety of applications, some of which involve automated handling of materials.
It has been the case for a number of years in the peptide field that use has been made of mechanized, computer-aided equipment capable of simultaneously synthesizing a number of different peptides by the sequential coupling of amino acids to functionalized solid supports. Such mechanized equipment may be employed because the conditions necessary for most such coupling reactions are uniformly simple and straightforward.
In the case of the synthesis of organic compounds generally, however, there is a great variance in the conditions and techniques which must be employed, which precludes or makes impractical the use of fully automated instruments. For example, magnetic stirring, shaking, or some other form of agitation may be needed, and heating or cooling to great temperature extremes may be required. With respect to reactions requiring heating, provision for the reflux of volatile solvent may also be necessary.
In addition, many chemical reactions are air sensitive and so may require an inert atmosphere, or a vacuum, for their performance. Reagents and substrates may be air sensitive (e.g., hygroscopic or pyrophoric) or corrosive. For such materials, it would extremely advantageous to use equipment in which the atmospheric conditions, or vacuum, may be easily provided without having to transfer materials into a vacuum chamber or glove box in order to allow manipulations.
The problem of manipulating material under such atmospheric conditions is compounded when the necessary manipulations include agitation of the materials, and/or heating of the contents. For some processes, vigorous agitation may be required which would be difficult to achieve in an open atmosphere without spillage, much less in an enclosure having a specialized atmosphere. For this reason, it would be desirable to seal the mouths of the individual wells while maintaining the required atmosphere.
One approach to the problem of maintaining a specialized atmosphere without having to use a bulky external vacuum chamber is to use a device having a gas-tight manifold which surrounds the device and may have ports for introduction of a controlled atmosphere. One prior art attempt is found in U.S. Pat. No. 5,324,483 issued Jun. 28, 1994 to Cody et al. In Cody, which is directed toward solid phase synthesis, the lower ends of a plurality of reaction tubes (in the nature of conventional gas dispersion tubes) are each received by a plurality of reaction wells. The reaction tubes are held vertically in place by a holder block, while the reactions wells are contained by a reservoir block. A seal is provided between the holder block and the reservoir block. A manifold covers the reaction tubes, with a seal being provided between the manifold and the holder block. Means are provided for detachably fastening together the reservoir block to the holder block and the holder block to the manifold. The dispersion tubes provide a glass frit type of filtering capability.
The invention in Cody has several draw-backs. The apparatus is bulky, and there is no way to seal the reaction tubes when vigorous agitation is required. For certain laboratory applications, mixing may be best accomplished by inverting the wells, so that the contents do not settle in layers. The apparatus in Cody has no sealing mechanism for the reaction tubes and thus obviously cannot be inverted without disastrous results. The volume of enclosed space within the manifold is not variable, and includes much more volume that is really necessary to charge the mouths of the reaction tubes with gas. Thus a greater than necessary volume of gas must be introduced and then purged, and in the case of toxic gases, disposed of safely. Some such gases may be expensive, and a savings in such usage may have a considerable impact on processing costs.
The size of the manifold volume may also have an impact on the creation of a vacuum for certain processing steps. The larger the volume to be evacuated, the larger the pump will have to be, to achieve the same vacuum in the same amount of time. Thus there may be cost savings in using a smaller volume.
Thus there is a need for an apparatus which can be used for multiple simultaneous synthesis on a micro scale, which allows for creation of an enclosed plenum which is adjustable in volume, and which can be easily configured to seal the mouths of all the wells simultaneously, thereby allowing the entire device to be inverted for agitation and mixing processes.
Accordingly, it is an object of the present invention to provide an apparatus for multiple simultaneous chemical and biological synthesis, chromatography, separation, extraction, analysis and processing on a micro scale which is simple to use.
It is another object of the invention to provide such an apparatus which is suitable for general organic synthesis, including provision for heating, agitation, addition by syringe, and the like.
It is a further object to provide such an apparatus which has a standard microplate footprint dimension and which is compatible with standard liquid handling and other batch processing equipment.
It is another object to provide such an apparatus which has a plenum of adjustable volume in which special atmospheric conditions or partial vacuums can be created.
It is a further object to provide such an apparatus in which the plenum volume can be adjusted to a minimum, so that the mouths of the wells can be simultaneously sealed.
It is yet a further object to provide such an apparatus which can be vigorously agitated without spillage of the contents of the apparatus.
It is yet another object to provide such an apparatus which can be completely inverted to allow for more complete mixing of materials without spillage.
It is an additional object of the invention that a plenum is provided which may be optionally adjustable between an open position and a closed position.
It is still another object of the present invention to provide an apparatus with a plenum which is continuously variable with respect to volume so that any volume within a defined range of volumes can be achieved, allowing flexibility of usage.
Briefly, the preferred embodiment of the present invention is an apparatus for multiple simultaneous synthesis, having a number of vials, each vial having an upper, a lower end, and a barrel, the upper end opening into a mouth portion. It also includes a lower frame assembly having a number of holes for receiving the vials, and an upper frame assembly, which includes inner side-walls and a ceiling portion. A gas-tight seal surrounds a plenum, the plenum being formed between the upper frame assembly ceiling portion, and the lower frame assembly. The plenum is adjustable in volume by the positioning of the upper frame assembly in variable relation to the lower frame assembly, while maintaining the gas-tight seal. The volume of the plenum is adjustable to a minimum whereby the mouths of the vials are sealed by the ceiling of the gas-tight seal, which is optionally an upper gasket.
Also disclosed is a plenum enclosure for multiple simultaneous synthesis used in conjunction with vials, which includes the upper and lower frame assembly and the a gas-tight seal, described in relation to the apparatus above. This plenum enclosure can be varied in design to accommodate vials of many different sizes, styles and manufactures.
An advantage of the present invention is that it allows a variety of gases to be introduced into the wells of the apparatus without having to relocate the apparatus to a specialized vacuum chamber or gas fill station.
Another advantage of the invention is that a vial holder gasket is provided which secures the included glass vials against movement.
A further advantage is that the same vial holder gasket is used to provide a gas-tight seal at the periphery of the plenum.
Yet another advantage is that the volume of the plenum is continually adjustable from a maximum volume down to a position where the mouths of all the reaction wells are simultaneously sealed.
Yet a further advantage is that the sealed reactions wells may then be vigorously agitated, and completely inverted without spillage of the contents.
Still another advantage is that the apparatus is designed to be attached into a rotating element and the entire apparatus is designed to be heated without damage to the apparatus.
Yet another advantage of the present invention is that after the reaction wells are sealed, the interiors of the wells may still be accessed through apertures aligned with the mouths of the reaction wells which are sealed with a gas-tight gasket which can be easily penetrated by a syringe needle, while still maintaining the gas-tight seal.
An additional advantage is that the present invention can work either with arrays of vials which are integrally fashioned into a unitary block, or with vials which are individually removable.
These and other objects and advantages of the present invention will become clear to those skilled in the art in view of the description of the best presently known mode of carrying out the invention and the industrial applicability of the preferred embodiment as described herein and as illustrated in the several figures of the drawings.